Gut Neuroendocrine Cell Signaling and Obesity

描述(由申请人提供)： 肥胖是一种常见、严重且代价高昂的疾病，33%的美国公民和37%的退伍军人症患者会受到影响。尽管治疗方法仍然难以捉摸，但最近的科学证据表明，肠道内分泌细胞--肠道的感觉细胞--是潜在的解决方案。已知这些细胞分泌几种能有效诱导饱腹感的神经肽，如CCK、GLP-1和YY(PYY)，它们的感觉机制一直是深入研究的主题。然而，这些细胞如何将它们的感觉信号传递到神经元和其他细胞在很大程度上是未知的。我们最近建立了新的转基因小鼠模型，通过在含有CCK或PYY的细胞中表达增强型绿色荧光蛋白(EGFP)来研究这些细胞。EGFP模型允许我们发现，肠内分泌细胞具有显著的基础细胞质突起，其特征与神经元轴突相似。我们发现，这些基本的细胞质突起直接连接到支配肠道粘膜的神经元传入和传出。本建议旨在阐明这一联系的作用。我们的中心假设是，在肠道内分泌细胞和感觉神经元之间的分子信息交换中，基本的细胞质过程是必不可少的。这一假说建立在PI实验室的初步数据基础上，并将通过追求以下特定目标来验证：�目标1是表征肠内分泌细胞和感觉神经元之间的联系�目标2是确定肠内分泌细胞胞浆突起的形成是如何调控的�目标3是确定饮食诱导的肥胖对神经-肠内分泌联系的影响我们预计肠道神经内分泌信号的特征将有助于制定策略来调节感觉信息从肠内分泌细胞到神经元的传输，反之亦然。因为这些感觉信号最终参与食物摄取和食欲的调节，阐明调节这种联系的机制可以为治疗肥胖症提供新的治疗方法。

DESCRIPTION (provided by applicant): Obesity is a common, serious, and costly disease that affects 33% of US citizens and 37% of VA patients. Although therapeutic treatments remain elusive, recent scientific evidence has pointed to enteroendocrine cells - sensory cells of the gut - as potential solutions. These cells are known to secrete several neuropeptides that are potent inducers of satiety, like cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), and their sensory mechanisms have been the subject of intensive investigation. However, how these cells transduce their sensory signals onto neurons and other cells is largely unknown. We recently developed novel transgenic mouse models to study these cells by expressing enhanced green fluorescent protein (eGFP) in CCK- or PYY-containing cells. The eGFP models allowed us to discover that enteroendocrine cells have prominent basal cytoplasmic processes with similar features to neuronal axons. These basal cytoplasmic processes, we found, directly connect to neuronal afferents and efferents innervating the gut mucosa. The present proposal is designed to elucidate the function of this connection. Our central hypothesis is that basal cytoplasmic processes are essential in the exchange of molecular information between enteroendocrine cells and sensory neurons. This hypothesis is built on preliminary data produced in the PI's laboratory and will be tested by pursuing the following specific aims: � Aim 1 is to characterize the connection between enteroendocrine cells and sensory neurons � Aim 2 is to determine how the formation of enteroendocrine cell cytoplasmic processes is regulated � Aim 3 is to define the effects of diet-induced obesity on the neuro-enteroendocrine connection We anticipate that the characterization of gut neuroendocrine signaling will facilitate the development of strategies to modulate the transmission of sensory information from enteroendocrine cells to neurons and vice versa. Because these sensory signals ultimately participate in the regulation of food intake and appetite, elucidating the mechanisms that regulate this connection can provide novel therapeutic approaches to treat obesity.